1. Field of the Invention
The present invention is concerned with a novel method of preparing statine, a naturally occurring amino acid, and closely related derivatives thereof.
Statine (Sta), which may be named as 4(S)-amino-3(S)-hydroxy-6-methylheptanoic acid, is an essential component of pepstatin, a naturally-occurring low-molecular-weight peptide first isolated from actinomyces and found to be a potent inhibitor of acid proteases such as pepsin, cathepsin D, and renin. See Umezawa et al., J. Antibiot. (Tokyo) 23: 259-262, 1970. The natural pepstatin pentapeptide contains two statine residues, and was found by Gross et al., Science 175: 656, 1971, to reduce blood pressure in vivo after the injection of hog renin into nephrectomized rats. Statine is also an essential component of certain novel renin inhibitory peptides described in applications Ser. Nos. 309,854 and 309,855, both filed Oct. 8, 1981; and Ser. No. 312,528, filed Oct. 19, 1981.
2. Brief Description of the Prior Art
The method of the present invention, like those utilized in the past to prepare statine, goes through an .alpha.-aminoaldehyde intermediate. However, unlike most such prior art methods, the method of the present invention utilizes a novel oxidative route to the .alpha.-aminoaldehyde intermediate which provides good overall yield and facility of preparing the statine final product.
For example, Steulmann and Klostermeyer, in Liebigs Ann. Chem 1975, 2245-2250, describe synthesis of BOC-L-leucinal by reduction of tert-butyloxycarbonyl-L-leucine imidazolide with LiAlH.sub.4. The ethyl ester of protected statine is then prepared by reacting the intermediate with the lithium compound of ethyl acetate. Alkaline saponification liberates the N-protected statine.
Kinoshita et al., Bull. Soc. Chem. Japan 48(2): 570-575 (1975), describe preparation of (-) (3S,4S) statine and its (+) (3S,4R) diastereomer starting from 3-deoxy-1,2-O-isopropylidene-.alpha.-D-erythro-pentodialdo-1,4-furanose.
Liu et al., J. Org. Chem. 43(4): 754 (1978) describe preparation of statine by means of a Reformatsky reaction sequence using the zinc enolate of tert-butyl acetate, starting with N-phthalyl-L-leucinal. They also describe an earlier statine synthesis reported in Morishima et al., J. Antibiot. 26:115 (1973). See also Liu et al., J. Med. Chem. 22(5): 577 (1979).
In all of the prior art methods referred to above, the protected chiral .alpha.-amino aldehyde intermediate is prepared by partial reduction of an L-leucine derivative. In fact, nearly all of the presently utilized methods for preparing chiral .alpha.-aminoaldehydes involve such a partial reduction approach. See Ito et al., Chem. Pharm. Bull. 23(12): 3081 (1975). See also Sharma et al., J.C.S. Chem. Comm. 1979: 875, who describe an exception involving periodate oxidation of diols.
One of the primary disadvantages of the prior art methods described above is the shortage of satisfactory methods for carrying out such selected reduction conveniently on a large scale and with retention of stereochemistry. For example, the most efficient method presently available for preparing statine uses a diisobutylaluminum hydride (Dibal) reduction of BOC-L-leucine ethyl ester to prepare the BOC-L-leucinal intermediate. See Rich et al., J. Org. Chem. 43: 3624 (1978). However, this method calls for rapid addition, followed by rapid quenching, of 1 M Dibal, carried out at low temperature. The total reaction time is reported to be 6 min. and the reaction temperature -78.degree. C. Thus, any attempt to scale up this method could pose technical problems.
Despite the drawbacks discussed above involving aldehyde synthesis based on partial reduction of carboxylic acid derivatives, little attention has been given to preparation of chiral .alpha.-aminoaldehydes by partial oxidation of carbinols. Preparation of aldehydes generally by different methods involving partial oxidation of carbinols is described in March, "Advanced Organic Chemistry: Reactions, Mechanism, and Structure," 2 ed.; McGraw-Hill: New York, 1977; pp. 1082-84. Perhaps one reason for the failure heretofore to employ the partial oxidation route to chiral .alpha.-aminoaldehydes is the presumed tendency of the media involved to racemize the sensitive aldehyde products.
In contrast to the methods of preparing statine and other .alpha.-aminoaldehydes employed in the past, the novel method of the present invention is rapid, convenient, and amenable to large scale work. The intermediate aldehyde is produced with nearly complete retention of chiral integrity.